Activation of Flk-1/KDR mediates angiogenesis but not hypotension.
OBJECTIVE
The concept of therapeutic angiogenesis with vascular endothelial growth factor (VEGF) has been validated in peripheral arterial disease. Its use in myocardial ischemia may be delayed as the result of the description in a porcine model of peripheral vasodilation after intraluminal injections of VEGF resulting in a 50% fatality rate by hypotension. We carried out this study to test whether VEGF-induced hypotension (1) is species specific, (2) is mediated by the receptor mediating angiogenesis, (3) is prevented by inhibition of nitric oxide synthase.


METHODS
In the rabbit corneal pocket assay we tested whether a previously published anti-idiotypic antibody (AIA) agonist of the VEGF receptor Flk-1/KDR could elicit angiogenesis. Various doses of recombinant VEGF or AIA were injected into anesthetized normotensive Wistar-Kyoto rats and the mean arterial blood pressure (MABP) was recorded. To test the implication of nitric oxide in VEGF-induced hypotension we treated the animals with a competitive inhibitor of nitric oxide synthase prior to the injection of VEGF.


RESULTS
Both VEGF and AIA induce angiogenesis but only intravenous injections of VEGF induced a rapid, transient and dose-dependent decrease in MABP. The ED50 was 0.5 micrograms. The interval between two VEGF injections required to lead to a decrease of MABP was 40 minutes. Nitric oxide synthesis inhibitor prevented, in a reversible fashion, the effect of VEGF.


CONCLUSIONS
VEGF-induced hypotension is not species specific. It is prevented by nitric oxide inhibition. VEGF-induced angiogenesis and hypotension are not mediated in vivo by the same VEGF receptor.
Malavaud
B
B
Laboratoire de Biologie Moléculaire Eucaryote/UPR CNRS 9006, Toulouse, France.
Tack
I
I
Jonca
F
F
Praddaude
F
F
Moro
F
F
Ader
J L
JL
Plouët
J
J
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011817:Rabbits; D051381:Rats; D011921:Rats, Inbred WKY; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D017978:Receptors, Growth Factor / Q000276:immunology*; D040262:Receptors, Vascular Endothelial Growth Factor; D018709:Statistics, Nonparametric; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000888:Antibodies, Anti-Idiotypic; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019323:omega-N-Methylarginine; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor